Not applicable.
The field of the invention is improved polyurethane compositions for in vitro and in vivo use, including calcification-resistant, thrombogenesis-resistant, and degradation-resistant polyurethanes.
Polyurethanes are polymers which can be made by condensing a diisocyanate with a diol, with two or more diols having different structures, or with both a diol and a diamine. For example, polyurethanes can be made as illustrated in FIGS. 1A and 1B. In FIG. 1A, a diisocyanate (OCNxe2x80x94Axe2x80x94CNO) is reacted with a diol (HOxe2x80x94Xxe2x80x94OH) to form a polyurethane. It is understood that the proportion of end groups corresponding to the diisocyanate and the diol can be controlled by using an excess of the desired end group. For example, if the reaction in FIG. 1A is performed in the presence of an excess of the diisocyanate, then the resulting polyurethane will have isocyanate (xe2x80x94NCO) groups at each end.
Depending on the identity of the reaction products used to form them, polyurethanes can behave as elastomers or as rigid, hard thermosets. If the diisocyanate depicted in FIG. 1A is, for example, 4,4xe2x80x2-methylenebis(phenylisocyanate), which has the following structure, 
then the region designated xe2x80x9cHSxe2x80x9d (i.e., xe2x80x98hard segmentxe2x80x99) in FIG. 1A will be relatively inflexible. If the diol depicted in FIG. 1A is, for example, polytetramethyleneoxide (i.e., HOxe2x80x94(CH2CH2CH2CH2O)kxe2x80x94H, wherein, e.g., k is about 10 to 30), then the region designated xe2x80x9cSSxe2x80x9d (i.e., xe2x80x98soft segmentxe2x80x99) will be relatively flexible. Methods of selecting polyurethane precursors which will yield a polyurethane having hard and soft segments which confer a desired property (e.g., flexibility, elastomericity, etc.) to the polyurethane are well known in the art.
As illustrated in FIG. 1B, methods of making segmented polyurethanes are also known in the art. In these methods, one or more types of polyurethane precursors (OCNxe2x80x94Pxe2x80x94NCO) are reacted with a chain extending compound (HZxe2x80x94Yxe2x80x94ZH) to yield a segmented polyurethane. By varying the proportions of different types of polyurethane precursors, their end groups, the identity of the chain extender, and the like, the composition of polyurethane segments in the segmented polymer can be controlled, as is known in the art.
Medical grade segmented polyurethanes are usually prepared as depicted in FIGS. 1A and 1B, by condensing a diisocyanate with a polymeric diol having a molecular weight of about 1,000 to 3,000 (e.g., polytetramethyleneoxide for polyether-urethanes or polycarbonatediols for polycarbonate-urethanes) in order to form a polyurethane precursor which is subsequently reacted with an approximately equivalent amount of a chain extender (e.g., a diol such as 1,4-butanediol or a diamine such as a mixture of diaminocyclohexane isomers).
Polyurethanes can be used to form bulk polymers, coatings, fillings, and films. They are also readily machinable once set. The properties of polyurethanes have rendered them useful for medical and non-medical purposes, and they have been used for such purposes since at least the beginning of the twentieth century. Medical uses of polyurethanes have, however, been heretofore limited by the tendency of polyurethane products which contact the blood stream or other biological fluids to calcify, induce thrombogenesis, and/or chemically and mechanically deteriorate. It is believed that polyurethane deterioration results, at least in part, from chemical breakdown of the block-copolymer structure of the polyurethane molecule.
Prior art methods of improving polyurethane stability have relied primarily upon two approaches. One approach involves incorporation into the polyurethane backbone of chain extending compound having groups to which substituents can be added. For example, condensation of the di-hydroxy compound 1,2-di-hydroxy-1,2-bis(diethoxyphosphinyl)ethane with diisocyanates yields a polyurethane having reduced flammability and having esterified phosphonic groups attached to the polymer backbone, as described (Mikroyannidis, 1984, J. Polymer Sci., Polymer Chem. Ed. 22:891-903). These polymers have potential drawbacks when used in biomedical applications because of reduced reactivity of the di-hydroxy chain extending compounds, relative to standard chain-extenders such as 1,4-butanediol. Thus, the molecular weight and mechanical properties of polymers modified in this manner may preclude their medical use.
Chain extending compounds having quaternary ammonium and phosphorylcholine groups have been used to prepare polyurethanes for medical purposes (Baumgartner et al., 1996, ASAIO J. 42:M476-M479). However it does not appear to be possible to insert non-esterified phosphonic groups into polyurethanes using 1,2-diols having such groups, presumably because of the ability of phosphonic hydroxyl groups to react with isocyanates. At the same time, cleavage of phosphonic esters attached to the backbone of the polymer would result in simultaneous cleavage of urethane bonds.
The second approach to stabilizing polyurethanes is based on N-alkylation of urethane amine groups of the polyurethane chain. Contacting a polyurethane with an alkylating agent in the presence of a strong base results in alkylation of the urethane amine groups of the chain to yield additionally-substituted amine groups. It is believed that the strong base serves to extract protons from the urethane nitrogen. It has been demonstrated that moderate grades of metallation with sodium hydride at temperatures not significantly exceeding 0xc2x0 C. do not induce significant polymer degradation (Adibi et al., 1979, Polymer 20:483-487). The polyanions remain soluble in aprotic solvents like dimethyl formamide and N,N-dimethylacetamide (DMA).
The first application of this N-alkylation method to medical grade polyurethanes involved N-alkylation of sodium hydride-activated polymer using alkyl iodides to attach C2 to C18 alkyl chains to the polymer backbone (Grasel et al., 1987, J. Biomed. Mat. Res. 21:815-842). It is believed that addition of such alkyl chains to polyurethanes improves the blood compatibility of the polymers. Grasel et al. pre-treated the polyurethane with sodium hydride at a temperature of from xe2x88x925xc2x0 C. to 0xc2x0 C., and the reaction of the activated polymer with alkyl iodides was performed at a temperature of about 50xc2x0 C. At this temperature, degradation of the polymer chain can occur. Further developments of such methods allowed substitution of the polymer chain with 3-carboxypropyl and 3-sulfonopropyl groups by activating the polyurethane chain using sodium hydride and then alkylating the chain using sodium salts of 4-iodobutyric acid or 1,3-propane sultone. Preparation of 3-carboxypropyl-modified polymers was complicated by the relatively low solubility of sodium 4-iodobutyrate in DMA. Another drawback to this method is that 4-iodobutyric acid, and alkyl iodides in general, are expensive and are not sufficiently stable in storage.
A need exists for methods of making improved polyurethane compositions which do not exhibit the utility-limiting effects exhibited by prior art polyurethanes. The present invention satisfies this need by providing polyurethane compositions which exhibit reduced thrombogenesis, reduced calcification, and greater resistance to chemical and mechanical deterioration.
The invention relates to apolyurethane composition comprising a polyurethane having a geminal bisphosphonate substituent pendant therefrom (e.g., from a urethane nitrogen of the backbone of the polyurethane). The geminal bisphosphonate substituent can, for example, be a sulfur-containing substituent or a nitrogen-containing substituent. Examples of the geminal bisphosphonate include moieities having the structural formula 
or an ionic form or salt of either of these,
wherein R1 an organic radical,
wherein X is selected from the group consisting of a C1 to C18 alkylene, a C1 to C18 alkenylene, a C1 to C18 arylene, a C1 to C18 alkylene having one or more O, S, or N atoms incorporated into the alkylene chain, a C1 to C18 alkenylene having one or more O, S, or N atoms incorporated into the alkenylene chain, and a heterocyclic radical, and
wherein Y is selected from the group consisting of hydrogen, hydroxyl, amino, C1 to C18 alkyl, C1 to C18 alkylamino, C1 to C18 alkoxy, C1 to C18 haloalkyl, C1 to C18 thioalkyl, C1 to C18 alkenyl, C1 to C18 aryl, C1 to C18 alkyl having one or more O, S, or N atoms incorporated into the alkylene chain, C1 to C18 alkenyl having one or more O, S, or N atoms incorporated into the alkenylene chain, and a heterocyclic compound.
R1 can, for example, be selected from the group consisting of C2 to C18 alkyl (preferably C2 to C6 alkyl or C2 to C4 alkyl), C2 to C18 alkylamino, C2 to C18 alkox, C2 to C18 haloalkyl, C2 to C18 thioalkyl, C2 to C18 alkenyl, C2 to C18 aryl, C2 to C18 alkyl having one or more O, S, or N atoms incorporated into the alkylene chain, C2 to C18 alkenyl having one or more O, S, or N atoms incorporated into the alkenylene chain, and a heterocyclic compound.
In one aspect, the polyurethane comprises at least about 10 micromoles of the geminal bisphosphonate substituent per gram of the polyurethane, such as a polyurethane wherein the geminal bisphosphonate substituent is pendant from at least about 0.5 to 40% of the urethane nitrogens of the backbone of the polyurethane.
Also included in the invention are polyurethane compositions, wherein the polyurethane has at least two different geminal bisphosphonate substituents pendant therefrom.
In another polyurethane composition of the invention, the polyurethane has both a geminal bisphosphonate substituent and a cationic substituent (e.g. a thioalkylamine moiety) pendant therefrom. When the cationic substituent is a thioalkylamine moiety, it can, for example, be a quaternary amine moiety or a moiety having the structural formula 
wherein R1 an organic radical,
wherein X is selected from the group consisting of a C1 to C18 alkylene, a C1 to C18 alkenylene, a C1 to C18 arylene, a C1 to C18 alkylene having one or more O, S, or N atoms incorporated into the alkylene chain, a C1 to C18 alkenylene having one or more O, S, or N atoms incorporated into the alkenylene chain, and a heterocyclic radical, and
wherein N1 is selected from the group consisting of xe2x80x94NH3, a primary organic amine moiety, a secondary organic amine moiety, and a tertiary organic amine moiety.
The invention further includes polyurethane composition as described herein, wherein the polyurethane is blended with a non-polyurethane polymer, and foams or implantable devices comprising a polyurethane composition described herein.
In another aspect, the invention relates to a method of making a geminal bisphosphonate-derivatized polyurethane. This method comprises
i) grafting a 1,xcfx89-dibromoalkyl compound (e.g., a C2-C6 1,xcfx89-dibromoalkyl compound) with a urethane amino moiety of a polyurethane to form an xcfx89-bromoalkyl-substituted polyurethane and
ii) grafting a geminal bisphosphonate thiol with the xcfx89-bromoalkyl-substituted polyurethane to form the geminal bisphosphonate-derivatized polyurethane. One advantage of this synthetic method is that it can be performed at a reasonable rate at a temperature lower than about 40 degrees Celsius. The method can be modified such that it further comprises grafting a thioalkylamine with the xcfx89-bromoalkyl-substituted polyurethane, in order to yield a derivatized polyurethane having both geminal bisphosphonate substituents and cationic substituents pending from its backbone.
Another method of making a geminal bisphosphonate-derivatized polyurethane comprises
i) grafting a xcfx89-bromocarboxylic acid (e.g., a C2-C6 xcfx89-bromocarboxylic acid) with a urethane amino moiety of a polyurethane to form an xcfx89-carboxyalkyl-substituted polyurethane and
ii) grafting a geminal bisphosphonate amine with the xcfx89-carboxyalkyl-substituted polyurethane to form the geminal bisphosphonate-derivatized polyurethane. This method can also be performed at a temperature lower than about 40 degrees Celsius, and can, like the method mentioned in the preceding paragraph, be modified such that it further comprises grafting a thioalkylamine with the xcfx89-carboxyalkyl-substituted polyurethane, in order to yield a derivatized polyurethane having both geminal bisphosphonate substituents and cationic substituents pending from its backbone.
In a hybrid method of making a geminal bisphosphonate-derivatized polyurethane
i) a 1 ,xcfx89-dibromoalkyl compound is grafted with a urethane amino moiety of a polyurethane to form an xcfx89-bromoalkyl-substituted polyurethane;
ii) the xcfx89-bromoalkyl-substituted polyurethane is contacted with an xcfx89-thiocarboxylic acid to form an xcfx89-carboxyl-thioalkyl-substituted polyurethane; and
iii) the xcfx89-carboxyl-thioalkyl-substituted polyurethane is grafted with a geminal bisphosphonate amine in order to form the geminal bisphosphonate-derivatized polyurethane.
The invention includes still another method of making a geminal bisphosphonate-derivatized polyurethane. This method comprises
i) grafting a bromo-epoxyalkyl compound (e.g., a C3-C6 bromo-epoxyalkyl compound) with a urethane amino moiety of a polyurethane to form an bromo-epoxyalkyl-substituted polyurethane and
ii) grafting a geminal bisphosphonate thiol with the bromo-epoxyalkyl-substituted polyurethane to form the geminal bisphosphonate-derivatized polyurethane. Like the methods mentioned above, this method can be performed at a reasonable rate at a temperature lower than about 40 degrees Celsius, and can be modified such that it further comprises grafting a thioalkylamine with the bromo-epoxyalkyl-substituted polyurethane, in order to yield a derivatized polyurethane having both geminal bisphosphonate substituents and cationic substituents pending from its backbone.
In still another aspect, the invention relates to a method of preparing a polyurethane derivative. This method comprises contacting a polyurethane with a bi-functional linker reagent in the presence of an aprotic solvent and a strong base to form an activated polyurethane derivative. The bi-functional linker reagent has a bromine substituent and a second functional group, and can, for example, be selected from the group consisting of a dibromoalkyl compound, a bromo-carboxyalkyl compound, and a bromo-epoxyalkyl compound. Examples of such bi-functional linker reagents include 1,6-dibromohexane, 1,4-dibromobutane, xcfx89-bromobutanoic acid, xcfx89-bromohexanoic acid, xcfx89-bromoundecanoic acid, and bromoalkyl oxirane compounds. The second functional group can, for example, be a geminal bisphosphonate group.